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Breast Cancer Contribution of the Prosigna ® (PAM50) Gene Signature Assay as a New-generation Genomic Test for Treatment Decision-making in Early Breast Cancer Nadia Harbeck, 1 Rachel Wuerstlein 1 and Karl Sotlar 2 1. Breast Center, Department of Obstetrics & Gynaecology, University of Munich and Comprehensive Cancer Center (CCC) of Ludwig-Maximilians-Universitaet (LMU), Munich, Germany; 2. Institute of Pathology, University of Munich, Munich, Germany Abstract The Prosigna ® Breast Cancer Prognostic Gene Signature Assay is based on the characterisation of 50 genes relevant to breast cancer biology and provides intrinsic subtype identification based on the individual tumour biology, a prognostic risk of recurrence (ROR) score and a risk group classification, for each individual patient tested. The Prosigna assay is indicated for post-menopausal women with early-stage hormone receptor-positive breast cancer with or without nodal involvement. Running on the NanoString nCounter ® DX Analysis system, which allows direct digital counting of target molecules, the assay offers a simple, reproducible and reliable method to profile many genes simultaneously with high sensitivity and precision. The Prosigna Breast Cancer Prognostic Gene Signature Assay has received 510(k) clearance from the US Food and Drug Administration. It has also received a CE mark and is available for use, among other geographical areas, in the EU, Israel and parts of the Middle East, through qualified local pathology laboratories. The de-centralised testing enables timely result delivery and direct interaction between the laboratory pathologists and treating physicians. The analytical reproducibility, precision and robustness of Prosigna have been demonstrated. Moreover, it has been clinically validated in two independent prospective- retrospective studies using >2,400 samples from post-menopausal patients enrolled in the Austrian Breast & Colorectal Cancer Study Group 8 (ABCSG 8) and Arimidex, Tamoxifen Alone or Combined (ATAC) trials (Level 1B Evidence). These validation studies show that Prosigna identifies a clinically relevant low-risk subgroup among both node-negative and node-positive patients with 1-3 involved lymph nodes. Moreover, the ROR score predicts risk of late distant recurrence as well as for high risk of local recurrence. Prosigna thus can offer clinically relevant information, which may help guide treatment decision-making in early breast cancer. Keywords Breast cancer, intrinsic subtypes, PAM50, risk of recurrence (ROR), analytical validation Disclosure: Nadia Harbeck has received honoraria for lectures from NanoString and for consulting from Genomic Health. Rachel Wuerstlein has received honoraria for lectures from NanoString and Genomic Health. Karl Sotlar has received speakers’ honoraria and travel support from NanoString. The authors are grateful for the editorial assistance provided by NanoString. Acknowledgements: Editorial assistance was provided by Catherine Amey at Touch Medical Media, funded by Nanostring. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 27 May 2015 Accepted: 6 September 2015 Citation: European Oncology & Haematology, 2015;11(2):85–91 Correspondence: Nadia Harbeck, Breast Center, University of Munich, Marchioninistraße 15, 80377 Munich, Germany. E: nadia.harbeck@med.uni-muenchen.de Support: Editorial support for this manuscript was provided by Nanostring. The opinions expressed are those of the authors and do not necessarily reflect those of Nanostring. Final approval of the manuscript and its content rested solely with the scientific authors. While the incidence of primary breast cancer has increased recently, most patients are diagnosed with early-stage disease and good prognosis. Around 80 % of patients with early breast cancer have estrogen receptor (ER)-positive disease and their prognosis will be improved substantially by endocrine therapy. 1 Nevertheless, the rate of distant recurrence (DR) in these patients can be as high as >20 % in the first 10 years and this rate can be reduced by adjuvant chemotherapy. 2 It is a priority in clinical breast cancer practice to differentiate patients at high risk of recurrence (ROR) from the majority at low risk (i.e. ≤10 % over 10 years) who may be spared chemotherapy. 3 The diversity in breast cancer, in terms of molecular alterations, cellular composition and clinical outcome, creates a challenge for developing tumour classifications that Tou ch MEd ica l MEdia are clinically useful for prognosis estimation. 4 The heterogeneity of breast cancer can be categorised into distinct subgroups called ‘intrinsic’ subtypes that are defined by their pattern of gene expression and clinical outcome: Luminal A, Luminal B, human epidermal growth factor 2 (HER2)-enriched and basal-like. 5,6 These intrinsic subtypes have been studied extensively, 6 9 and the St Gallen International Expert Consensus has recognised that these intrinsic subtypes provide key information for treatment decision-making in early breast cancer. 10,11 The intrinsic subtypes were first identified and long studied using genome-wide RNA expression profiling or DNA microarrays, and fresh frozen tissue. In order to identify the original intrinsic subtypes using the clinically relevant formalin-fixed paraffin-embedded (FFPE) 85